Production of sulphathiazole



Patented Jan. 11, 1944 PRODUCTION OF SULPHATHIAZOLE Leonard ChristieLeitch and Leo Brickman,

Montreal, Quebec, and Leo Edward Ryan, Dorval, Quebec, Canada, assignorsto Mallinckrodt Chemical Works Limited, Montreal, Quebec,

Canada No Drawing. Application April 11, 1942, Serial No. 438,586. InCanada July 5, 1941 11 Claims. (01. 260-302) This invention relates tothe production of sulphathiazole, and is particularly directed to a newand improved method of synthesizing the product whose properties make ituseful in therapeutic applications.

The object of the invention is to provide a method wherebysulphathiazole ma be made available in pure form and more economicallythan is possible by heretofore known methods.

In accordance with the invention sparingly soluble aminothiazole saltsof certain sulphonic acids are coupled, in the presence of a tertiaryamine, such as pyridine, quinoline, a dialkylaniline or pyridine basesin general, with a derivative of benzenesulphonyl halide having in thepara position one of the following: N02, a, halogen, an azo group, or-NHR where R represents an acyl roup. The following are illustrative ofthe sulphonic acids from which the aminothiazole salts may beformed-m-nitrobenzenesulphonic acid, 2-chloro-p-cymene-3-(or -5)sulphonic acid, p-cymene-Z-(or -3) s 111 p h o ni acid,o-chloro-p-toluenesulphonic acid and soluble salts of such acids.

In utilizing such salts rather than the free amine there is avoided thenecessity of isolating the aminothiazole from the reaction mixture inwhich it is formed, as for example by the method disclosed in UnitedStates Patent 2,230,962. Moreover, further economy is obtained throughthe higher yield Of sulphathiazole produced by the present method andthe precipitants may be recovered readily from the mother liquors afterthe salt is coupled with the sulphonic acid.

The following examples illustrate how the invention may be carried outin practice but the invention is not to be limited by the specificdetails given therein.

(1) To a hot solution of 25 grams of sodium 2-chloro-p-cymene-3-(or -5)sulphonate dissolved in 200 cc. of water was added 50 cc. ofaminothiazole hydrobromide liquor, as produced for example by the methodof the above mentioned patent. Afterboiling for a few minutes withcarbon black the solution was filtered, and the salt which crystallizesfrom the filtrate on cooling was collected, washed with cold water, anddried. The yield is 24-25 grams. The crude salt may be purified byrecrystallization from water or alcohol. It then melts at 200-201 C.

To the crude salt mixed with 50 cc. or pyridine there was graduallyadded 12 grams of p-acetaminobenzene-sulphonyl chloride, and the mixturewas heated at 95 C. to: 2 hours. The solvent was removed in vacuo, andthe acetylsulphathiazole isolated by adding 200 cc. of water andfiltering oflE the solid. Yield 9.8 grams, melting point 248 C.

(2) To a hot solution of 25 grams of sodium cymene-B-sulphonate in cc.of water was added 50 cc. of aminothiazole hydrobromide liquor. Theamine salt separated immediately and was filtered off, and washed withcold water. Yield 18.3 grams, meltin point -171 C.

17 grams of the crude salt in 25 cc. of pyridine wa treated with 12grams of p-acetaminobenzenesulphonyl chloride, and the mixture heatedfor 2 hours at 95 C. The acetylsulphathiazole was isolated as in theprevious example. Yield 8.7 grams, melting point 249 C.

(3) To 17 grams of sodium m-nitrobenzenesulphonate dissolved in 50 cc.of water was added to 50 cc. of aminothiazole hydrobromide liquor. Theprecipitated salt was washed with 10 cc. of saturated sodium chloridesolution and dried. Yield 18 grains, melting point 180 C.

To 18 grams of this salt mixed with 25 cc. of pyridine was added 13.5grams of p-acetaminobenzenesulphonyl chloride and the mixture was heatedfor 2 hours at 95 C. The acetylsulphathiazole was isolated as beforewith a yield of 12.5 grams, melting point 246 C.

(4) To 25 grams of sodium o-chloro-p-toluenesulphonate dissolved in 100cc. of Water was added 100 cc. of aminothiazole hydrobromide liquorgiving a yield of 21.2 grams of the amine salt having amelting point of192 C.

12 grams or" this amine salt in 20 cc. of pyridine and 9 grams ofp-acetyiaminobenzenesuipnonyi chloride were heated for 2 hours at 95 C.to yield 9.3 grams or the sulphatniazole having a meltin point of 251 C.

(5) 15 grams of aminothiazole 0-ch1orot0l'uene-p-sulionate is mixed with10 cc. o1 pyridine, 25 cc. or acetone, and 12 grams ofp-acetaminobenzenesulionyl chloride. 'i'he mixture is heated iour hours,and then the acetone is distilled on. After removing the pyridine invacuo the residue is treated with 100 cc. or distilled water, and thelight DIOWD. precipitate oi acetyisuiphatmazole is filtered on anddried. Yield: 8.2 grams, melting point 246".

(6) To 30 grams of aminothiazole o-chlor-ptoluene-sulphonate in 50 cc.of pyridine is added with snalnng 21.1 grams of p-nitro-benzenesulphonylchloride and the mixture is heated for about two hours at 90 C. Thesolvent is removed in vacuo and the residue treated with 200 cc. of

water to isolate 24 grams of p-nitro-benzenesulphonamidothiazole, whichis converted to sulphathiazole by reducing the nitro group to the amino.

(7) 30 grams of iaminothiazole o-chlor-p-toluene-sulphonate and 21 gramsof p-chlorbenzenesulphonyl chloride heated for two hours at about 95 C.in the presence of pyridine yields 24 gramsp-chlorbenzenesulphonamidothiazole.

The coupling reaction may be illustrated as follows:

Aminothiazole salt of the sulphonic acid plus benzenesulphonyl halidederivative, in the presence of a tertiary amine solvent, yields theacetyl or other sulphathiazole. structurally the coupling reaction maybe illustrated thus s OzCl on s\ 01 H emotion-Gone Tertiary CHN Aminewhere X='NO2, Cl, azo, or NHR where R is an acyl group.

The iacetyl or other sulphathiazole product is converted to the sulphathiazole. The acetylsulphathiazole is hydrolyzed to sulphathiazole byany of the standard procedures using aqueous alkalies or mineral acids.Where the nitro or azo group replaces the acylamino. group,sulphathiazole may be obtained by reduction with hydrogen. Where ahalogen is present in the intermediate, it may be converted tosulphathiazoleby treatment with aqueous or alcoholic ammonia underpressure and at elevated temperatures.

Instead of the liquor containing the aminothiazole in the form ofbromide, or chloride, any other soluble salt, such as the acetate,nitrate or sulphate may be used. It will be observed that the directprecipitation with the aminothiazole salts of. the sulphonic acidsdescribed yield the aminothi azole salt in a state of purity for directcoupling, and avoids tedious extraction. and re-. crystallization withthe losses incident thereto. In order to recover the precipitant afterthe coupling, the mother liquors thereof are rendered alkaline with acaustic alkali, or carbonate and evaporated to a small volume, fromwhich the salt crystallizes in nearly quantitative yield on cooling.

While particular details have been, given, in the examples it is to beunderstood that the invention isnot limited thereto except as set forthin the appended claims. Forexarnple the reaction may be carried out attemperatures of 20 to 110 C.

We claim:

1.. A method of preparing sulphathiazole which comprises causingaminothiazole salts of sulphonc acids to react, in the presence of atertiary amine, with a derivative of benzenesulphonyl halide having inthe para position one of the following-N02, ahalogen, an azo group andNHR Where R repressents an acyl group.

2. A method as defined in claim 1 wherein the mixture is heated atsubstantially 95 C. for about two hours.

3. In the production of sulphathiazole, the method which comprisesforming an aminothiazole salt of one of a group consisting ofm-ni'trobenzenesulphonic acid, 2-ch1oro-p-cymene-3-(or -5) sulphonicacid, p-cyrnene-Z-(or -3) sulphonic acid, o-chloro-p-toluenesulphonicacid and their soluble salts, and heating the resulting salt in thepresence of a solvent having :a pyridine base with a derivative ofbenzenesulphonyl halide having in the para position one of a group ofsubstituents consisting of N02, a halogen, an azo group, and NHR where Rrepresents an acyl group.

4. A method as set forth in claim 3 wherein said heating is continuedfor about 2 hours at about 95 C.

5. In the production of sulphathiazole, the method which comprisesreacting, in the presence of a solvent having a pyridine base,p-acetoamidobenzenesulphonyl chloride with an aminothiazole salt of oneof a group consisting of m-nitrobenzenesulphonic acid,2-ch1oro-p-cymene-3-(or -5) sulphonic acid, p-cymene-Z-(or -3) sulphonicacid, o-chloro-p-toluenesulphonic acid and their soluble salts andhydrolyzing the product.

6. A method as defined in claim 3 wherein. the

precipitating aminothiazole salt of said group is the presence of atertiary amine, and, hydrolyzing the acetylsulphathiazole formed tosulphathiazole.

9. A method as defined in claim 3 wherein the reaction product formedwith they substituent in the para position consisting of one of a groupconsisting of N02 and an iazo group is reduced,

to form sulphathiazole.

10. A method as defined in claim 3 wherein the reaction product formedwith the substituent in the para position consisting of a halogen istreated with ammonia to form sulphathiazole.

11. A method as defined in claim 1 wherein the reaction product formedwith the substituent in the para position including an acyl group ishydrolyzed to form sulphathiazole.

LEONARD CHRISTIE LEITCH. LEO BRICKMAN. LEO EDWARD RYAN.

